The present invention relates to new pyrimidin-4-one compounds, and to pharmaceutical compositions containing them.
The invention relates also to their use as combined xcex12/5-HT2c ligands.
1,2,3,3a,4,9b-Hexahydrochromeno[3,4-c]pyrrole compounds have been described in Patent Application EP 691 342 in terms of their serotoninergic antagonist character and in Patent Application EP 887 350 in terms of their D3 dopaminergic ligand character.
The corticolimbic structures play an essential part in the processes controlling the altered functions in psychiatric disorders. In particular, it is now recognised that disturbance of monoaminergic transmission is strongly implicated in the aetiology of those various disorders. For example, in the case of depression, monoaminergic activity is reduced in the frontal cortex, the hippocampus and the nucleus accumbens.
Among the various classes of auto- and hetero-receptors of monoamines implicated in the mechanisms of regulation, xcex12-AR (autoreceptor) and 5-HT2c receptors have been found to be of major importance. Those two receptor sub-types act in the same direction by inhibiting dopaminergic and adrenergic transmission. On the one hand, retro-control is exerted by xcex12-AR (autoreceptor) receptors on noradrenergic neurons (J. Pharmacol. Exp. Ther., 1994, 270, 958), and, on the other hand, xcex12-AR receptors and 5-HT2c heteroreceptors exert inhibitory control on dopaminergic and noradrenergic transmission (Neuropharmacology, 1997, 36, 609, J. Psychopharmacol. 2000, 14 (2), 114-138).
Compounds binding to one or other of those receptor sub-types have, in the past, demonstrated their potential for the treatment of a number of pathologies.
For example, the beneficial role of xcex12-AR antagonist compounds has been studied in the treatment of cognitive disorders (J. Pharmacol., 1992, 6, 376), Parkinson""s disease (CNS Drugs, 1998, 10, 189), schizophrenia (Science 1999, 286, 105-107), depression (J. Psychopharmacol. 1996, 10 Suppl. 3, 35-42), disturbances of libido, and sexual dysfunctions (J. Pharmacol., 1997, 11, 72). Likewise, 5-HT2c receptor ligands have demonstrated their usefulness in the treatment of sexual dysfunctions (J. Pharmacol., ibid.) and Parkinson""s disease (Drug News Perspect., 1999, 12, 477), as well as anxiety (Br. J. Pharmacol., 1996, 117, 427), depression (Pharmacol. Biochem. Behav. 1988, 29, 819-820), impulsive disorders (Biol. Psych. 1993, 33, 3-14), appetite disorders (British J. Pharmacol. 1998, 123, 1707-1715), sleep disorders (Neuropharmacology 1994, 33 (3/4), 467-471) and schizophrenia (Neurosci. Lett., 1996, 181, 65).
Compounds having a double xcex12-AR and 5-HT2c antagonist character may be highly useful to clinicians in obtaining, by administration of a single compound, a reinforced action whilst improving tolerability. A compound of that kind, moreover, has a considerable advantage over the administration of two different compounds.
The compounds of the invention have a novel structure providing them with their double xcex12/5-HT2c antagonist character and are therefore useful in the treatment of depression, impulsive behaviour disorders, anxiety, schizophrenia, Parkinson""s disease, cognitive disorders, disturbances of libido, sexual dysfunctions, appetite disorders and sleep disorders.
The present invention relates to compounds of formula (I): 
wherein:
R1, R2, R3 and R4, which may be the same or different, each represent a hydrogen atom, a halogen atom or a group selected from linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)polyhaloalkyl, hydroxy, cyano, nitro and amino,
xe2x80x83or R1 with R2, R2 with R3, or R3 with R4, together with the carbon atoms carrying them, form an optionally substituted benzene ring or an optionally substituted heteroaromatic ring,
X represents an oxygen atom or a methylene group,
A represents a linear or branched (C1-C6)alkylene chain, 
xe2x80x83represents an unsaturated nitrogen-containing heterocycle optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)polyhaloalkyl, cyano, nitro, amino, optionally substituted phenyl, optionally substituted thienyl, optionally substituted furyl and optionally substituted pyrrolyl groups,
and R5 represents a linear or branched (C1-C6)alkyl group,
to their enantiomers and diastereoisomers, and to addition salts thereof with a pharmaceutically acceptable acid or base,
it being understood that:
the term xe2x80x9c(C1-C6)alkylxe2x80x9d denotes a hydrocarbon chain containing from one to six carbon atoms,
the term xe2x80x9c(C1-C6)alkoxyxe2x80x9d denotes a (C1-C6)alkyl-oxy group containing from one to six carbon atoms,
the term xe2x80x9c(C1-C6)alkylenexe2x80x9d denotes a bivalent hydrocarbon chain containing from one to six carbon atoms,
the term (C1-C6)polyhaloalkyl denotes a carbon chain containing from one to six carbon atoms and from 1 to 9 halogen atoms,
the term xe2x80x9cheteroaromatic ringxe2x80x9d denotes a 5- or 6-membered aromatic ring containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur,
the term xe2x80x9cunsaturated nitrogen-containing heterocyclexe2x80x9d denotes a 5- to 7-membered unsaturated ring having one, two or three unsaturations and containing one, two or three hetero atoms, one of those hetero atoms being the nitrogen atom and the additional hetero atom(s) optionally present being selected from oxygen, nitrogen and sulphur atoms,
the term xe2x80x9coptionally substitutedxe2x80x9d applied to the expressions xe2x80x9cbenzene ringxe2x80x9d, xe2x80x9cheteroaromatic ringxe2x80x9d, xe2x80x9cphenylxe2x80x9d, xe2x80x9cthienylxe2x80x9d, xe2x80x9cfurylxe2x80x9d or pyrrolylxe2x80x9d indicates that those groups are optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)polyhaloalkyl, cyano, nitro and amino groups.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid etc.
Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine etc.
Among the heteroaromatic rings there may be mentioned, without implying any limitation, thiophene, pyridine, furan, pyrrole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrmidine.
Preferred unsaturated nitrogen-containing heterocycles are 1,2-dihydropyridine, 2,3-dihydro-1,3-thiazole and 2,3-dihydro-oxazole.
A (3axcex1,9bxcex1) or (3axcex2,9bxcex2) compound is understood to mean a compound wherein the relevant ring junction is of the cis configuration.
A (3axcex1,11cxcex1) or (3axcex2,11cxcex2) compound is understood to mean a compound wherein the relevant ring junction is of the cis configuration.
A (3axcex1,9bxcex2) or (3axcex2,9bxcex1) compound is understood to mean a compound wherein the relevant ring junction is trans.
A (3axcex1,11cxcex2) or (3axcex2,11cxcex1) compound is understood to mean a compound wherein the relevant ring junction is trans.
In preferred compounds of formula (I), R1, R2, R3 and R4, which may be the same or different, each represent a hydrogen atom or a linear or branched (C1-C6)alkyl, linear or branched (C1-C6)alkoxy or hydroxy group.
Preferred compounds of the invention are those wherein R1 and R2, together with the carbon atoms carrying them, form a benzene ring and R3 and R4 each represent a hydrogen atom.
X preferably represents an oxygen atom.
The invention advantageously relates to compounds of formula (I) wherein A represents an ethylene, propylene or butylene chain.
The invention more especially relates to compounds of formula (I) wherein 
represents the following group 
optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)polyhaloalkyl, cyano, nitro, amino and thienyl groups.
Other preferred compounds of the invention are compounds of formula (I) wherein 
represents the following group 
optionally substituted by one or two identical or different substituents selected from halogen atoms and linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)polyhaloalkyl, cyano, nitro and amino groups.
The present invention more especially relates to compounds of formula (I) wherein A represents an ethylene chain, X represents an oxygen atom, R5 represents a methyl group and 
represents the following group 
optionally substituted in the 2xe2x80x2-position by a halogen atom or a group selected from linear or branched (C1-C6)alkyl, cyano and thienyl.
The invention relates most especially to the following compounds:
3-[2-((3axcex1,9bxcex1)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2 (3H)-yl)-ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,
3-[2-((3axcex1,11cxcex1)-1,3a,4,11c-tetrahydrobenzo[5,6]chromeno[3,4-c]pyrrol-2(3H)-yl-ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one,
and 3-[2-((3axcex2,11cxcex1)-1,3a,4,11c-tetrahydrobenzo[5,6]chromeno[3,4-c]pyrrol-2 (3H)-yl)ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that a compound of formula (II): 
wherein R1, R2, R3, R4 and X are as defined for formula (I),
is subjected to catalytic hydrogenation to yield the compound of formula (III): 
wherein R1, R2, R3, R4 and X are as defined hereinbefore,
which is reacted either with a compound of formula (IV): 
wherein A, B and R5 are as defined for formula (I) and Y1 represents a leaving group such as, for example, a halogen atom or a tosylate, triflate or mesylate group,
or, under conditions of reductive amination, with a compound of formula (V): 
wherein B and R5 are as defined for formula (I) and Axe2x80x2 represents a bond or a linear or branched (C1-C5)alkylene chain,
to yield the compound of formula (I), which is purified, if necessary, according to a conventional purification technique, which is separated, if desired, into its stereoisomers according to a conventional separation technique, and which is converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid or base.
The compounds of formula (II) wherein X represents an oxygen atom (compounds of formula (IIa)) may be obtained starting from the compound of formula (VI): 
wherein R1, R2, R3 and R4 are as defined hereinbefore, which is subjected to cycloaddition with N-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine under conditions described by K. Achiwa et al. (Chem. Pharm. Bull. 1985, 33 (7), 2762-66),
to yield the compound of formula (VII): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is then converted, by reduction followed by deprotection of the phenol function, into the compound of formula (VIII): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is then converted into the compound of formula (IIa) by a Mitsunobu reaction.
The configuration of the ring junction of the compound of formula (IIa) thereby obtained is determined by the configuration (Z or E) of the compound of formula (VI) used.
The compounds of formula (IIa) may also be obtained starting from the compound of formula (IX): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is oxidised into the compound of formula (X): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is reacted with methyl propiolate to yield the coumarin of formula (XI): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is subjected:
either, when it is desired to prepare a compound of formula (IIa) wherein the ring junction is trans, to reaction with sodium methanolate and then to a cycloaddition reaction with N-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine under conditions described by K. Achiwa et al. (Chem. Pharm. Bull. 1985, 33 (7), 2762-66), followed by a reduction reaction,
xe2x80x83to yield a compound of formula (VIII) whose configuration is trans,
xe2x80x83which is then converted into a trans compound of formula (IIa) by a Mitsunobu reaction,
or, when it is desired to prepare a compound of formula (IIa) wherein the ring junction is cis, to a cycloaddition reaction with N-benzyl-N-(methoxymethyl)-trimethylsilylmethylamine under conditions described by K. Achiwa et al. (Chem. Pharm. Bull. 1985, 33 (7), 2762-66),
to yield the compound of formula (XII) whose ring junction is cis: 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is then reduced to form a compound of formula (VIII) whose configuration is cis, which is then converted into a cis compound of formula (IIa) by a Mitsunobu reaction.
The compounds of formula (II) wherein X represents a methylene group (compounds of formula (IIb)) may be obtained starting from the compound of formula (XIII): 
wherein R1, R2, R3 and R4 are as defined for formula (I),
which is reacted with ethyl acrylate to yield the compound of formula (XIV): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is converted, by reduction followed by hydrolysis, into the compound of formula (XV): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is cyclised to form the compound of formula (XVI): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is then converted into the compound of formula (XVII): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
and then, by addition of lithium cyanide, into the compound of formula (XVIII): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
the cyano groups of which are converted into carboxy groups before being condensed to yield the compound of formula (XIX): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is then reacted with benzylamine to yield the compound of formula (XX): 
wherein R1, R2, R3 and R4 are as defined hereinbefore,
which is converted, by reduction, into the compound of formula (IIb).
The present invention relates also to pharmaceutical compositions comprising as active ingredient a compound of formula (I) together with one or more inert, non-toxic, pharmaceutically acceptable excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) or nasal administration, tablets or dragxc3xa9es, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions etc.
The useful dosage can be varied according to the nature and severity of the disorder, the administration route and also the age and weight of the patient and any associated treatments. The dosage varies from 0.5 mg to 2 g per 24 hours in one or more administrations.
The following Examples illustrate the invention but do not limit it in any way.
The starting materials used are known products or are prepared according to known methods of preparation.
The structures of the compounds described in the Examples have been determined by conventional spectrometric techniques (infra-red, NMR, mass spectrometry).